Littérature scientifique sur le sujet « Cardioautonomic function, beta cell insulin secretion, type 2 diabetes »

Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.

It is well known that beta-cell function declines over time in adults with type 2 diabetes mellitus (T2DM). The beta-cell dysfunction, initially characterized by impairment in the first phase of insulin secretion following glucose stimulation, advances to a decline in second phase insulin secretion as the disease progresses. But whether this decline in beta-cell function occurs in adolescents with T2DM is uncertain. Investigators prospectively compared beta-cell functioning over time between 39 adolescents with newly diagnosed T2DM (mean age, 15 years; body-mass index z-score, 2.4) and 32 obese adolescents without T2DM of comparable body-mass index, gender, and race (mean age, 14) during a 2-year period. Recently, researchers from Duke University School of Medicine, Durham North Carolina reported that adolescents with newly diagnosed T2DM had a 25% annual decline in beta-cell function despite receiving treatment. In this study, the results of which were first presented at the American Diabetes Association (ADA), the participants were adolescents with T2DM, more than half of whom were being treated with insulin whereas 80% were taking oral anti-diabetes medications. Beta-cell function in this study, assessed at baseline and 6, 12, and 24 months was measured by insulin secretion in response to an intravenous glucose load adjusted for insulin sensitivity (disposition index). The authors observed that adolescents with T2DM had significantly higher levels of both insulin resistance and fasting glucose at baseline compared with controls. But during the two-year study, the study subjects experienced a significant increase in fasting glucose and a 25 percent annual decline in disposition index. Understandably, both these indicators remained unchanged among the controls. JMS 2017;20(2):116

Aims Previous studies suggest that small intestinal bacterial overgrowth (SIBO) is associated with type 2 diabetes. However, few studies have evaluated the association between SIBO and beta-cell function in type 2 diabetes. The aim of this study was to evaluate whether beta-cell function was associated with SIBO. Materials and methods One hundred four patients with type 2 diabetes were included in this study. Based on the presence of SIBO, the patients were divided into SIBO-positive and SIBO-negative groups. Oral glucose tolerance tests were performed. Insulin sensitivity was measured using 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and the insulin sensitivity index (ISIM). Insulin release was calculated by HOMA-β, early-phase insulin secretion index InsAUC30/GluAUC30, and total-phase insulin secretion index InsAUC120/GluAUC120. Results Compared with the SIBO-negative group, patients in the SIBO-positive group showed a higher glucose level at 120 minutes, HbA1c, 1/HOMA-IR, and ISIM and a lower HOMA-β level, early-phase InsAUC30/GluAUC30, and total-phase InsAUC120/GluAUC120. Multiple linear regression analysis showed that body mass index, glucose at 0 minutes, and SIBO were independently associated with the early-phase and total-phase insulin secretion. Conclusion SIBO may be involved in lower levels of insulin release and worse glycemic control.

Diabetes type 2 is a chronic metabolic disorder. Pathogenesis of diabetes type 2 results from the impaired insulin secretion, impaired insulin action and increased endogenous glucose production. Diabetes evolves through several phases characterized by qualitative and quantitative changes of beta cell secretory function. The aim of our study was to analyze the impact of diabetes duration on beta cell secretory function and insulin resistance. The results indicated significant negative correlation of diabetes duration and fasting insulinemia, as well as beta cell secretory function assessed by HOMA ? index. Our study also found significant negative correlation of diabetes duration and insulin resistance assessed by HOMA IR index. Significant positive correlation was established between beta cell secretory capacity (fasting insulinemia and HOMA ?) and insulin resistance assessed by HOMA IR index, independently of diabetes duration. These results indicate that: beta cell secretory capacity, assessed by HOMA ? index, significantly decreases with diabetes duration. In parallel with decrease of fasting insulinemia, reduction of insulin resistance assessed by HOMA IR index was found as well.

Pineal hormone melatonin synchronizes insulin secretion and glucose homeostasis with solar periods. Misalliance between melatonin-mediated circadian rhythms and insulin secretion characterizes diabetes mellitus type 1 (T1DM) and type 2 (T2DM). Insulin deficiency in T1DM is accompanied by increased melatonin production. Conversely, T2DM is characterized by diminished melatonin secretion. In genome-wide association studies the variants of melatonin receptor MT2 gene (rs1387153 and rs10830963) were associated with fasting glucose, beta-cell function and T2DM. In experimental models of diabetes melatonin enhanced beta-cell proliferation and neogenesis, improved insulin resistance and alleviated oxidative stress in retina and kidneys. However, further investigation is required to assess the therapeutic value of melatonin in diabetic patients.

This review deals with the role of adipose tissue inflammation (ATI) in the development of type 2 diabetes mellitus (DM2). ATI is regarded as a link between obesity and DM2. The review illustrates the involvement of main adipokines in pathogenesis of DM2 and provides a detailed description of such factors as impaired adiponectin and stimulation of cytokine production responsible for metabolic disorders, activation of lipolysis, in adipocytes, increased fatty acid and triglyceride levels, suppression of insulin activity at the receptor and intracellular levels. Adipokines, in the first place cytokines, act on the insulin signal pathway and affect the intracellular inflammatory kinase cascade. At the intercellular level, ATI stimulates JNK and IKK-beta/kB responsible for the development of insulin resistance via such mechanisms as activation of cytokine secretion in the adipose tissue, oxidative stress, and induction of endoplasmic reticulum enzymes. The key role of JNK and IKK-beta/kB in the inhibition of the insulin signal pathway is mediated through inactivation of insulin receptor substrate 1. Also, it is shown that ATI modulates B-cell function and promotes progressive reduction of insulin secretion.

There is an increasing concern that chemicals in the environment are contributing to the global rise in the prevalence of type 2 diabetes (T2D). However, there is limited evidence for direct effects of these chemicals on beta cell function. Therefore, the goals of this study were (1) to test the hypothesis that environmental contaminants can directly affect beta cell function and (2) examine mechanistic pathways by which these contaminants could affect beta cell function. Using mouse beta TC-6 cells, we examined the acute effects of 6 substances (benzo[a]pyrene, bisphenol A [BPA], propylparaben, methylparaben, perfluorooctanoic acid, and perfluorooctyl sulfone) on insulin secretion. Only BPA treatment directly affected insulin secretion. Furthermore, chronic exposure to BPA altered the expression of key proteins in the cellular and endoplasmic reticulum stress response. These data suggest that long-term BPA exposure may be detrimental to beta cell function and ultimately be an important contributor to the etiology of T2D.

Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.

The pancreatic beta cell is a highly specialized cell type whose primary function is to secrete insulin in response to nutrients to maintain glucose homeostasis in the body. As such, the beta cell has developed unique metabolic characteristics to achieve functionality; in healthy beta cells, the majority of glucose-derived carbons are oxidized and enter the mitochondria in the form of pyruvate. The pyruvate is subsequently metabolized to induce mitochondrial ATP and trigger the downstream insulin secretion response. Thus, in beta cells, mitochondria play a pivotal role in regulating glucose stimulated insulin secretion (GSIS). In type 2 diabetes (T2D), mitochondrial impairment has been shown to play an important role in beta cell dysfunction and loss. In type 1 diabetes (T1D), autoimmunity is the primary trigger of beta cell loss; however, there is accumulating evidence that intrinsic mitochondrial defects could contribute to beta cell susceptibility during proinflammatory conditions. Furthermore, there is speculation that dysfunctional mitochondrial responses could contribute to the formation of autoantigens. In this review, we provide an overview of mitochondrial function in the beta cells, and discuss potential mechanisms by which mitochondrial dysfunction may contribute to T1D pathogenesis.

Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.

Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet β cells. However, the role and sequence of β cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of β cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, β cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained β cell volume further declines. These results indicate that dysfunction of persisting β cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy.

Background: type 2 diabetes is determined by a reduction of β cell mass and function besides a defect in insulin sensitivity. It was demonstrated that pancreatic islets are innervated by sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) fibers and autonomic function contributes to the regulation of glucose homeostasis. An alteration in neuronal control of β cell function could be involved in the pathogenesis of the type 2 diabetes. Aim: we focused on finding a possible association between autonomic function and the different parameters that describe β cell function in The Maastricht Study, a population-based cohort. We sought this association also in the population of Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), a study of patients with newly diagnosed type 2 diabetes. Research design and Methods: in the Maastricht study population from 24-h electrocardiogram we derived Heart Rate Variability (HRV) time and frequency domains (individual z-scores, based upon seven and six variables, respectively). From a standard 2-hour 75 g OGTT we estimated different aspects of β cell function, i.e. C-peptidogenic index t0-30, overall insulin secretion, β cell glucose sensitivity, β cell potentiation factor, and β cell rate sensitivity, using formula-based methods and mathematical modeling. In the VNDS study cardiovascular autonomic function was assessed by a computerized system which analyzed heart rate and blood pressure variations during lying to standing (LS), deep breathing (DB), and Valsalva maneuver (VM), following the criteria presented by Ewing and Clarke. From a 5-hour 75g OGTT we estimated through mathematical modelling two main parameters of beta cell glucose sensitivity: derivative (first phase) and proportional control (second phase) of insulin secretion. Results: in the Maastricht study we analyzed 2007 individuals with a mean  standard deviation (SD) age of 59.8  8.2 years, of whom 52% were men and 24% with type 2 diabetes (oversampled by design). After adjustment for age, sex, educational level and Matsuda index, time and frequency domain HRV were significantly and directly associated with C-peptidogenic index, β cell glucose sensitivity and β cell potentiation factor, but not with overall insulin secretion. Then, further adjustment for cardiovascular risk factors (model 4) did not materially alter these associations, though only the association of HRV with C-peptidogenic remained statistically significant (standardized β [95%CI] per 1-SD increment in HRV TIME domain, for respectively C-peptidogenic index, overall insulin secretion, β cell glucose sensitivity, and β cell potentiation, 0.05 [0.00; 0.09]; 0.04 [-0.00; 0.08]; 0.04 [0.00; 0.08] ; and 0.04 [-0.00; 0.08]; standardized β [95%CI] per 1-SD increment in HRV FREQUENCY domain, for respectively C-peptidogenic index, overall insulin secretion, β cell glucose sensitivity, and β cell potentiation, 0.05 [0.00; 0.09]; 0.04 [-0.00; 0.08]; 0.04 [0.00; 0.08] ; and 0.04 [-0.00; 0.08]). HRV time and frequency domain weren’t significantly associated with rate sensitivity. Furthermore, we evaluated data of 537 patients with newly diagnosed type 2 diabetes with a mean ± SD age of 58.3 ± 9.6 of whom 66.3% were male. 91 subjects (16.9%) showed at least one abnormal test used to evaluate cardiovascular autonomic function (CAN). We found a worse derivative control of beta cell function in people with signs of cardio autonomic neuropathy as compared to the other group. This difference however did not reach statistical significance (p=0.063). Conclusion: In summary, in the present research we analyzed a possible association between autonomic function and β cell secretion, estimated from OGTT. We found that autonomic dysregulation could contribute to β-cell dysfunction, in particular affecting the first phase of insulin secretion. This mechanism could add to the other factors that lead to the impairment of glucose homeostasis.

Endocrine complications after bariatric surgery include persistent hyperglycemia in patients with type 2 diabetes who experience initial success with weight loss. This complication occurs in those with a prolonged duration of diabetes (> 8 years) and is related to poor residual pancreatic beta-cell function. Often, weight regain is associated with recurrent diabetes, and strategies that target both weight loss and glycemic control are required. New diabetes agents, such as the SGLT2 inhibitor drug class, offer advantages to diabetes treatment after bariatric surgery. On the other end of the glycemic spectrum, hyperinsulinemic hypoglycemia occurs in patients with and without diabetes prior to surgery and often presents with little or no symptoms (i.e., neuroglycopenia). Treatment strategies involve careful monitoring of blood glucose levels and the use of low-glycemic/high-fiber diets as well as drugs that lower glucose absorption and insulin secretion. Glycemic management after bariatric surgery requires close observation.

A selection of differently acting blood glucose-lowering agents can be used in the management of type 2 diabetes to address different aspects of disease pathogenesis and comorbidities. Key factors influencing choice of medication include extent and duration of hyperglycaemia, obesity, insulin resistance, and impairment of beta-cell function, risk of hypoglycaemia, and risk or presence of cardiovascular, renal, and other complications. Diet, other lifestyle measures, patient education, and empowerment are fundamental throughout. Metformin is still widely used as initial orally administered blood glucose-lowering therapy. Other orally administered agents include sulphonylureas and meglitinides which stimulate insulin secretion, sodium/glucose cotransporter-2 (SGLT2) inhibitors which increase glucose elimination in the urine, thiazolidinediones which improve insulin sensitivity, and alpha-glucosidase inhibitors which slow the rate of carbohydrate digestion. Dipeptidylpeptidase-4 (DPP4) inhibitors slow the degradation of endogenous incretins, particularly glucagon-like peptide-1 (GLP-1), potentiating prandial insulin secretion, and reducing excess glucagon secretion. GLP-1 receptor agonists, which are administered by subcutaneous injection further increase prandial insulin secretion, reduce hyperglucagonaemia, and facilitate weight loss.

Type 2 diabetes is characterized by chronic hyperglycaemia. This results from decreased pancreatic beta-cell function and impaired insulin action, together with raised circulating glucagon levels and changes in the entero-insular axis. Headway is being made to define the mechanisms that underlie these pathophysiological changes. The combined effects of common but functionally weak genetic susceptibility variants constitute the major genetic predisposition to type 2 diabetes. While the majority of the genetic variants are related to altered insulin secretion, a proportion influence insulin action by altering adipose tissue distribution. At the cellular level, mechanisms are emerging that are common across the different tissues, including ectopic fat deposition and lipotoxicity, and the activation of pro-inflammatory pathways. The metabolic derangement in type 2 diabetes extends to altered lipid metabolism and the development of non-alcoholic fatty liver disease. Understanding the mechanisms that lead to type 2 diabetes will inform the development of future therapies.